Relaxin and fibrosis: Emerging targets, challenges, and future directions

Abstract

The peptide hormone relaxin is well-known for its anti-fibrotic actions in several organs, particularly from numerous studies conducted in animals. Acting through its cognate G proteincoupled receptor, relaxin family peptide receptor 1 (RXFP1), serelaxin (recombinant human relaxin) has been shown to consistently inhibit the excessive extracellular matrix production (fibrosis) that results from the aberrant wound-healing response to tissue injury and/or chronic inflammation, and at multiple levels. Furthermore, it can reduce established scarring by promoting the degradation of aberrant extracellular matrix components. Following on from the review that describes the mechanisms and signaling pathways associated with the extracellular matrix remodeling effects of serelaxin (Ng et al., 2019), this review focuses on newly identified tissue targets of serelaxin therapy in fibrosis, and the limitations associated with (se)relaxin research.

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

“…A total of 40 signaling pathways were identified. In the most significantly altered signaling pathway in this study, fibrosis was reported in previous studies to be involved in the ‘Hedgehog signaling pathway’ ( 35 – 37 ), ‘ABC transporters’ ( 38 ), ‘ErbB signaling pathway’ ( 39 , 40 ), ‘cAMP signaling pathway’ ( 41 , 42 ), ‘Relaxin signaling pathway’ ( 43 , 44 ), ‘Ras signaling pathway’ ( 45 , 46 ) and ‘PI3K-Akt signaling pathway’ ( 47 , 48 ). Additionally, six ECM-associated pathways were directly associated with renal fibrosis.…”

Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation

“…But we have not been able to examine the efficacy of RLX-2 on pre-existing fibrosis. RLX-2 is expected to use in various fibrous diseases [11], and is also known to enhance heart function with dilating peripheral blood vessels, and clinical research was held as a therapeutic agent for heart failure [46]. Although further study is needed, RLX-2 can be expected to be a new therapy for endometriosis with various effects.…”

“…In the endometriosis mouse model (Figure 5a), administration of RLX-2 significantly decreased the area of the endometriotic-like lesion compared to the non-treated control (p = 0.01, Figure 5b). As RLX-2 has an anti-fibrotic potential [11], the extent of fibrosis in the mouse endometriotic-like lesions was evaluated using the Masson trichrome staining method. As shown in Figure 5c, fibrous tissues, which are stained with light blue, were decreased in the RLX-2 group compared to the control.…”

“…Recently, relaxin (RLX)-2 has attracted significant interest for its anti-fibrotic effect in various fibrous diseases of the heart, lungs, kidneys, and bladder [11]. RLX-2 is a peptide hormone belonging to the insulin superfamily that has a collagenolytic effect [11,12]. In women, RLX-2 is secreted from the corpus luteum and placenta, and the role of RLX-2 during labor has been studied extensively.…”

“…However, the effect of RLX-2 on endometriosis remained unclear. Since RLX-2 has been shown to be a potential treatment for various fibrotic diseases [11], we conducted this study on the hypothesis that RLX-2 could be an effective treatment for endometriosis.…”